Drug discovery articles within Nature

Featured

  • Outlook |

    Finding the right food to help reduce our chances of cancer can be a maze. But ongoing studies and a little inventive cooking might point us in the right direction.

    • Sarah DeWeerdt

  • Outlook |

    Being able to determine an individual's chances of developing cancer will greatly improve risk management strategies and recruitment to clinical trials.

    • Vicki Brower

  • Letter |

    Lung cancers with activating mutations in EGFR can be treated with EGFR inhibitors, but not all tumours respond and some develop resistance. In an RNAi screen, this study searches for modifiers of the EGFR inhibitor response. It is found that inhibition of FAS and NF-κB signalling enhances the response in vitro and in vivo. In a cohort of lung cancer patients treated with EGFR inhibitors, expression of the NF-κB inhibitor IκB is associated with a better response and longer survival, indicating that combining NF-κB pathway and EGFR inhibitors may prove clinically useful.

    • Trever G. Bivona
    • , Haley Hieronymus
    •  & Charles L. Sawyers

  • Letter |

    In a zebrafish model of melanoma driven by activated BRAF, this study finds expression of a gene signature indicative of disrupted terminal differentiation of neural crest progenitors. A chemical screen led to the identification of leflunomide as an inhibitor of neural crest stem cells. Leflunomide inhibits dihydroorotate dehydrogenase and thereby transcriptional elongation, including genes involved in neural crest development and melanoma growth. Leflunomide has anti-melanoma activity in the zebrafish model and human melanoma xenografts, and might prove useful as an anticancer drug.

    • Richard Mark White
    • , Jennifer Cech
    •  & Leonard I. Zon

  • Editorial |

    US biomedical scientists should support bold plans to transform the process of drug development. Now is not the time for disunity.

  • Letter |

    This study solves the X-ray crystal structure of a constitutively active mutant of rhodopsin, a G-protein-coupled receptor, bound to a peptide derived from the C-terminus of the G protein transducin. Comparison of this structure with the structure of ground-state rhodopsin suggests how translocation of the retinal β-ionone ring leads to a rotational tilt of transmembrane helix 6, the critical conformational change that occurs upon activation.

    • Jörg Standfuss
    • , Patricia C. Edwards
    •  & Gebhard F. X. Schertler

  • News Q&A |

    For GlaxoSmithKline's research chief Patrick Vallance, drug development unites in-house depth with external breadth.

    • Daniel Cressey

  • Letter |

    Substantial risk for schizophrenia is conferred by large copy number variants at a number of genomic loci. Here, a significant association between duplications on chromosome 7 and schizophrenia is reported. Importantly, microduplication analysis narrowed down the region to a region just upstream of a gene encoding vasoactive intestinal peptide receptor (VIPR2). Increased expression of VIPR2 in patients with schizophrenia implicates VIP signalling as a molecular mechanism underlying schizophrenia.

    • Vladimir Vacic
    • , Shane McCarthy
    •  & Jonathan Sebat

  • Comment |

    Most protein research focuses on those known before the human genome was mapped. Work on the slew discovered since, urge Aled M. Edwards and his colleagues.

    • Aled M. Edwards
    • , Ruth Isserlin
    •  & Frank H. Yu

  • News & Views Forum |

    Two approaches have emerged for creating libraries of compounds for use in biological screening assays for drug discovery — fragment-based ligand design and diversity-oriented synthesis. Advocates of each approach discuss their favoured strategy.

    • Philip J. Hajduk
    • , Warren R. J. D. Galloway
    •  & David R. Spring

  • Letter |

    The mechanism of action of general anaesthetics is poorly understood, although there is some evidence that their principal protein targets are pentameric ligand-gated ion channels (pLGICs). Here, the X-ray crystal structures of propofol and desflurane bound to a bacterial homologue of the pLGIC family are solved. The structures reveal a common binding site for these two anaesthetics in the upper part of the transmembrane domain of each protomer.

    • Hugues Nury
    • , Catherine Van Renterghem
    •  & Pierre-Jean Corringer

  • News |

    Heart disorder joins growing list of conditions getting the 'disease in a dish' treatment.

    • Ewen Callaway

  • Letter |

    Here, the X-ray crystal structure of the β1 adrenergic receptor, a G-protein-coupled receptor, bound to four small molecules that either act as full agonists or partial agonists is solved. The structures show that agonist binding induces a contraction of the catecholamine-binding pocket relative to the antagonist-bound receptor. This work reveals the pharmacological differences between different ligand classes, which should facilitate the structure-based design of new drugs with predictable efficacies.

    • Tony Warne
    • , Rouslan Moukhametzianov
    •  & Christopher G. Tate

  • Article |

    The X-ray crystal structure of the human β2 adrenergic receptor, a G-protein-coupled receptor, in an agonist-bound 'active' state is solved. Comparison of this structure with a previously published structure of the same GPCR in an inactive state indicates that minor changes in the binding pocket of the protein lead to major changes elsewhere — there is a large outward movement of the cytoplasmic end of one of the transmembrane segments and rearrangements of two other transmembrane segments. This structure provides insights into the process of agonist binding and activation.

    • Søren G. F. Rasmussen
    • , Hee-Jung Choi
    •  & Brian K. Kobilka

  • News & Views |

    Protein factors can regulate gene expression by binding to specifically modified DNA-associated proteins. Small molecules that selectively interfere with such interaction may be of therapeutic value. See Article p.1067 & Letter p.1119

    • Sean D. Taverna
    •  & PhiliP A. Cole

  • Editorial |

    Moves to price new pharmaceuticals sensibly shouldn't damage the industry's health.

  • Letter |

    Post-translationally modified histones are recognized by effector proteins which contain specific binding modules; for example, the bromodomain-containing BET proteins bind acetylated lysine residues during gene activation. Here a synthetic small molecule is described that interferes with the binding of certain BET family members to acetylated histones. The compound inhibits activation of pro-inflammatory genes in macrophages and has activity in a mouse model of inflammatory disease.

    • Edwige Nicodeme
    • , Kate L. Jeffrey
    •  & Alexander Tarakhovsky

  • Letter |

    Systemic amyloidosis is a serious disease caused by accumulation of amyloid fibrils in the viscera and connective tissues. Serum amyloid P component (SAP) is a normal plasma protein that concentrates within the amyloid deposits. These authors find that a combination of a drug that depletes circulating SAP and an antibody that targets residual SAP within the deposits results in clearance of amyloid deposits in a mouse model of the disease.

    • Karl Bodin
    • , Stephan Ellmerich
    •  & Mark B. Pepys

  • Editorial |

    An increasing number of biomedical researchers are testing their ideas on people. The early-phase clinical-trial results are a promising sign of greater cooperation between scientists and clinicians.

  • Article |

    A new approach is used to target BET family bromodomains which are found in transcriptional regulators where they mediate the recognition of acetyl-lysine chromatin marks. Structural data reveal how the compound JQ1 binds to the bromodomain of BRD4. BRD4 has been implicated in a subtype of human squamous carcinomas, and JQ1 is found to inhibit the growth of BRD4 dependent tumours in mouse models.

    • Panagis Filippakopoulos
    • , Jun Qi
    •  & James E. Bradner

  • Letter |

    PLX4032 is a selective inhibitor of the B-RAF protein that has shown promising results in an early clinical trial in melanoma patients with an activating mutation in B-RAF. Now the structure and function of this inhibitor are described. Translational data from a phase I trial show that clinical efficacy requires a substantial degree of inhibition of the ERK pathway downstream of B-RAF. The data also show that BRAF-mutant melanomas are highly dependent on B-RAF activity.

    • Gideon Bollag
    • , Peter Hirth
    •  & Keith Nolop

  • Letter |

    A major hallmark of Alzheimer's disease is the accumulation in the brain of amyloid-β peptide. This is generated by γ-secretase, which is thus of interest as a target for drugs to prevent amyloid-β accumulation. A problem is that γ-secretase has other substrates, including Notch, important in development. Here, a γ-secretase activating protein is identified that increases amyloid-β production without affecting Notch. Thus this protein can serve as an amyloid-β-lowering drug target without affecting other functions of γ-secretase.

    • Gen He
    • , Wenjie Luo
    •  & Paul Greengard

  • News & Views |

    Presenilin proteins have a major role in normal cellular processes, but some contribute to disease, for example through the formation of amyloid-β. The way in which these different roles are regulated is now becoming clearer.

    • Peter St George-Hyslop
    •  & Gerold Schmitt-Ulms

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